Triaryl-ethenes



United States Patent ()fiice Patented Jan. 2%, 1953 3,675,971 TRHARYL-ETEENE3 I William Laszlo Eencze, Summit, Null, assignor to Ciba Corporafion, a corporation of Delaware No Drawing. Filed Apr. 27, 195?, Ser. No. 808,914 6 Claims. ((Il. zen-n40 The present invention concerns styrene-type compounds. More particularly, it relates to compounds oi the iormula in which at least one of the radicals R and R represents a heterocyclic aryl radical, and the other a heterocyclic aryl radical or a carbocyclic aryl radical, R stands for a monocyclic carbocyclic aryl radical, substituted by a group of the formula OAZ, in which Z represents a tertiary amino group and A a lower alkylene radical, and the radical R represents hydrogen or lower alkyl, salts and quaternary ammonium compounds, as well as process for the preparation thereof.

A heterocyclic aryl radical R or R represents a bicyclic, or primarily a monocyclic heterocyclic aryl radical, the hetero atom of which may be sulfur, or particularly nitrogen. One or more hetero atoms, particularly nitrogen atoms, may form part of the heterocyclic nucleus. Preferred are monocyclic heterocyclic aryl radicals, which contain one or two nitrogen atoms as members of the heterocycle. Such radicals are primarily Z-pyridyl, 3- pyridyl or 4-pyridyl radicals; 3-pyridazinyl, 2-pyrimidyl, 4-pyrimidyl or Z-pyrazinyl radicals represent groups with two nitrogen atoms as members of the monocyclic heterocyclic aryl nucleus. The heterocyciic radical is preferably unsubstituted; possible substitutents may be, for example, lower aliiyl, e.g. methyl or ethyl, lower alkoxy, e.g. methoxy, or halogen, e.g. chlorine or bromine.

If only one of the radicals R and R is represented by a heterocyclic aryl radical, the other radical stands for a carbocyclic aryl radical, particularly a monocyclic carbo, cyclic aryl radical, which may be unsubstituted or substituted by one or more substituents in any of the available positions. Substituents may be represented by lower alkyl, e.g. methyl or ethyl, lower alkoxy, e.g. methoxy or ethoxy, lower alkylenedioxy, e.g. methylenedioxy, lower alkyl-mercapto, e.g. methylmercapto or ethylmercapto, nitro, amino, such as tertiary amino, for example, dilower alkyl-amino, e.g. dimethylamino, halogen, e.g. fluorine, chlorine or bromine, or polyhalogeno-lower alkyl, e.g. trifluoromethyl. Substituted monocyclic carbocyclic aryl radicals are, therefore, for example, lower alkylphenyl, lower alkoxy-phenyl, lower alkylenedioxy-phenyl, lower a kyl-mercapto-phenyl, nitro-phenyl, amino-phenyl, (ii-lower alkyl-amino-phenyl, halogeno-phenyl, or polyhalogeno-lower alkyl-phenyl.

The monocyclic carbocyclic radical R is substituted by a tertiary amino-lower alkoxy group of the formula O.AZ

which may be located in any of the available positions, but substitutes preferably the 4-position.

In a tertiary amino-lower alkyi radical of the formula -AZ the tertiary amino group Z is particularly an N,N- di-lower hydrocarbon-amino, an N,N-lower alkyleneimino, an N,N-lower oxa-alkylene-imino, an N,N-lower thia-alkylene-imino or an N,N-lower aza-alkylene-imino group. Lower hydrocarbon radicals of an N,N-di-lower hydrocarbon-amino groups .are, for example, lower alkenyl, lower cycloalkyl, carbocyclic aryl, carbocyclic arylelower alkyl, or primarily lower alkyl radicals containing from one to seven carbon atoms. Such radicals a are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, allyl, methallyl, cyclopentyl, cyclohexyl, phenyl or benzyl. Therefore, N,N-di-lower hydrocarbonamino groups are particularly represented by N,N-di-lower alkyl-amino, e.g. dimethylamino, diethylamino, clipropylamino or diisopropylamino groups, or, in addition, by N-methylfN-cyclopentylamino or N-methyl- N-benzylamino groups. The lower alkylene portion of N,N-lower alkylene-imino, N,N-lower oxa-alkylene-imino, N,N-lower thia-alkylene-imino or N,N-lower aza-. alkylene-imino groups contains preferably from four to six carbon atoms. Together with the nitrogen atom such lower alkylene, lower oxa-alkylene, lower thia-alkylene or lower aza-alkylene radicals represent, for example, pyrrolidino radicals, e.g. pyrrolidino or Z-methyl-pyrolidino, piperidino radicals, e.g. piperidino, Z-methyl-piperidino, 3-methyl-piperidino, 4-methyl-piperidino, 3-hydroxy-piperidino, 3-acetoxy-piperidino or 3-hydroxymethyl-piperidino, hexamethyleneimino, morpholino, thiamorpholino, or piperazino radicals, e.g. 4-methyl-piperazino, 4-hydroxyethyl-piperazino or 4-acetoxyethyl-piperazmo.

The lower alkyl portion A of a tertiary amino-lower alkyl radical of the formula -A-Z represents a lower alkylene radical, which contains preferably from two to three carbon atoms and separates the tertiary amino group from the oxygen atom of the tertiary amino-lower alkoxy group of the formula O,AZ by at least two carbon atoms. Lower alkylene radicals representing this group A are primarily 1,2-ethylene, 1-methyl-1,2-ethylene, 2; methyl-1,2-ethylene or 1,3-propylene.

In addition to the substituent ,O-AZ the mono.- cyclic carbocyclic aryl group R may contain other sub-v stituents, such as, for example, lower alkyl, e.g. methyl or ethyl, lower alkoxy, e.g. methoxy or ethoxy, lower alkylenedioxy, e.g. methylenedioxy, lower alkyl-mercapto, e.g. methylmercapto or ethylmercapto, nitro, amino, such as tertiary amino, for example, di-lower alkyl-amino, e.g. dimethylamino, halogen, e.g. fluorine, chlorine orbromine, or polyhalogeno-lower alkyl, e.g. trifiuoromethyl.

The radical R represents primarily hydrogen; when standing for lower alkyl, it may primarily be methyl.

Salts of the compounds of this invention are particularly therapeutically acceptable acid addition salts with inorganic acids, particularly mineral acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric or phosphoric acids, or with organic acids, for example, organic carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, succinic, maleic, hydroxymaleic, dihydroxymaleic, furamic, malic, tartaric, citric, benzoic, cinnamic, mandelic or salicylic acid, or organic sulfonip acids, e.g. methane sulfonic, ethane sulfonic or 2-hydroxy ethane sulfonic acid. Mono or poly-salts may be formed, depending on the procedure used for the preparation of the salts and the number of salt forming groups present in the molecule.

Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by aliphatic hydroxy-compounds with strong acids; such acids are particularly mineral aoids, such as hydrohalic acids, e.g. hydrochloric, hydrobromic or bydriodic acids, or organic sulto-nic acids, such as lower alkane sulfonic acids, e.g. methane or ethane sulionic acid or lower hydroxy-alkane sulfonic acid, e.g. Z-hydroxyethane sulfonic acid. Such esters are especially lower alkyl halides, e.g. methyl, ethyl, propyl or isopropyl chloride, bromide or iodide, lower alkyl loyer allgane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate, or lower alkyl hydroxy-lower alkane sulfonates, e.g. methyl Z-hydroxyethane sulfonate. Also included as quaternary ammonium componnds are the quaternary ammonium hydroxides, and the salts of such quaternary ammonisprees:

um hydroxides with inorganic, or particularly with organic carboxylic or sulfonic acids, such as with those described hereinbefore as being suitable for the preparation of acid addition salts. Monoor poly-quaternary ammonium compounds may be formed, depending on the reaction conditions used and the number of tertiary amino groups present in the molecule. The compounds of the present invention exhibit antiutero-tropic or anticstrogenic eit'ects, They may, therefore, be used, for example, as anti-fertility agents to prevent the fertilization of the ovum. They may also beneficially influence so-called collagen diseases, such as gout, lupus erythromatosis, Stills disease, osteoporosis or related conditions.

in addition, the compounds of this invention may affect the relative distribution of cholesterol in the body and toy, therefore, be used in the treatment of arteriosclerosis, atherosclerosis and similar conditions.

Particularly useful are compounds of the formula in which at least one of the radicals R and R represents a pyridyl radical, and the other stands for a pyridyl radical or a monocyclic carbocyclic aryl radical, which may be unsubstituted or substituted by lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or halogen, e.g. chlorine or bro-mine, 3., stands for hydrogen or methyl, A represent a lower allcylene radical, having from two to three carbon atoms and separating the tertiary amino group 2 from the oxygen atom by at least two carbon atoms, and Z stands for N,i -di-lower alkyl-arnino, in which lower alkyl has from one to four carbon atoms, or N,N- lower alkylene-imino, N,N-lower oXa-alkylene-imino or PLN-lower aza-alkylene irnino, the allrylene radicals of which contain from four to six carbon atoms, and acid addition salts with mineral acids or aliphatic lower bydrocarbon monocarboxylic, aliphatic lower hydrocarbon dicarboxylic or aliphatic lower hydroxy-hydrocarhon dicarboxylic acids. This series of compounds may be illustrated by the following groups of compounds having the formulae:

in which formulae Py represents pyridyl, Ph stands for phenyl, methyl-phenyl, methoxy-phenyl, chloro-phenyl or bromo-phenyl, A represents a lower allzylene radical contairing from two to three carbon atoms and separating the group Z from the oxygen atom by at least two carbon atoms, and Z stands for N,N-di-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, and acid addition salts with mineral acids, lower alltane carhoxylic acids, lower alkene dicarboxylic acids or lower hydroxy-alkane dicarboxylic acids.

The compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, wh ch contain the new derivatives or salts thereof in admixture with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration. For making up the prepara tions there may be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other known carrier for medicarneuis. The pharmaceutical preparations may be in the solid form, for example, as capsules, tablets or dragees, or in liquid form, for example, as solutions, suspensions or emulsions. if desired, they may contain auxiliary substances, such as preserving agents, stabilizing agents, wetting or emulsifying agents, salt for varying the osmotic pressure or butters 'i" hey may also contain in combination other therapeutically useful substances.

The compounds of this invention may be prepared by dehydrating compounds of the formula OHO AER

in which R R R and R have the previously-given meaning, and, if desired, converting a resulting salt into the free base, and/or, if desired, converting a resulting free base into a salt or a quaternary ammonium compound thereof.

Dehydration of the tertiary alcohols of the above given formula may be achieved according to methods used for analogous procedures. For example, treatment of the tertiary alcohol with an acidic reagent may ailord the loss of water. Such acidic reagents may be of inor ganic nature, and are primarily, mineral acids,- e.g. hydrochloric, sulfuric or phosphoric acid. These acids may be employed according to dilferent procedures: gaseous acids, such as hydrogen chloride, may be passed in gas-' eous form through a solution of the tertiary alcohol in a lower alkanol, e.g. ethanol or propanol, or acetic acid, or may first be dissolved in one of these solvents and then given to the tertiary alcohol; sulfuric acid may housed in its concentrated aqueous form and phosphoric acid as polyphosphoric acid. Other dehydration reagents are inorganic acid halides, such a thionyl chloride, which may be employed in solution with an inert solvent, such as a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene or toluene. Organic acids, which may split off water from the tertiary alcohol, are monocyclic carbocyclic aryl sulfonic acids, e.g. p-toluene sulfonic acid, which may be used together with a water separator to remove the generated water. The reaction is carried out under cooling at room temperature or at an elevated temperature, if necessary, under pressure or in the atmosphere of an inert gas, e.g. nitrogen.

The resulting product may be isolated by extraction, absorption and elution, crystallization, etc. and purified by recrystallization, salt formation, etc. The tertiary alcohols used as the starting materials for the preparation of the compounds of the present invention may be prepared by reacting a ketone of the formula ort m in which R and R have the previously-given meaning,

and M represents the positive ion of certain metals of the lA-group of the periodic system or the positive ion of a mono-halide of certain divalent metals of the ILA- group and the EB-group of the periodic system.

M represents primarily the positive ion of an alkali metal, such as sodium, or particularly lithium, or the positive ion of a mono-halide of magnesium. Alkali metal derivatives are preferably used with those compounds, in which R represents a heterocyclic aryl radical, and R represents hydrogen or lower alkyl, or in which R, stands for a carbocyclic aryl radical and R repr sents lower alkyl, whereas the ma lesium halide-type reagent (Grignard reagent) is especially useful with compounds, in which R stands for a carbocyclic aryl radical and R represents hydrogen.

Both types of reagents are used under similar conditions; preferably, the alkali metal compound or the Grignard reagent is prepared separately and i then reacted with the keto-ne. The solvent present durin the preparation of the reagent, primarily diethyl ether, may also be used in the condensation reaction or may be diluted or replaced by other suitable solvents, for example, other others, such as monocyclic carbocyclic aryl lower alkyl others, e.g. anisole, bis-monocyclic carbocyclic aryl others, e.g. diphenyl ether, cyclic ethers, e.g. tetrahydrofuran or p-dioxane, organic bases, e.g. pyridine or N-methylmorpholine, monocyclic caroocyclic aryl hydrocarbons, e.g. benzene or toluene, or aliphatic hydrocarbons, e.g. pentane or hexane. The reaction may be carried out and completed under cooling, at room temperature, or while heating, and the atmosphere or an inert gas, cg. nitrogen, may be required, particularly when alkali metal reage ts are used.

The reagents used for the preparation of the starting materials it ay be known or may be prepared according to methods used for the preparation of known analogs.

For example, reagents of the formula QH M in which R, has the previously-given meaning, R represents a heterocyclic aryl radical and M stands for the positive ion or an alkali metal, particularly a lithium ion, may be prepared by reacting the compound of the formula R --CH R with an organic alkali metal compound, such as, for example, phenyl sodium, phenyl lithium or n-butyl lithium, preferably in the presence of an inert solvent, such as an ether, e.g. diethyl ether or tetrahydrofuran, or an aliphatic hydrocarbon, eg. hexane, and in the atmosphere of an inert gas, e.g. nitrogen. Similarly, reagents of the formula:

on n

in which R represents a carbocyclic aryl radical, R; stands for lower alkyl and M represents the positive ion of an alkali metal, especially a lithium ion, may be obtained by treating with lithium and at temperatures below 0 C. a dilute soluL'on of an ether of the formula:

in which Y may stand for lower alkyl, e.g methyl, carbocyclic aryl, e.g. phenyl, or carbocyclic aryl-lower alkyl, e.g. the radical of the formula:

in which R, and K, have the above-given meaning, in an inert solvent, especially an ether, e.g. tetrahydrofurane. This latter procedure may also be used for the manufac-. ture of alkali metal reagents of the formula:

in which R represents a carbocyclic aryl radical and M stands for the positive ion of an alkali metal.

However, for the introduction of a carbocyclic arylmethyl radical the use of a Grignard reagent of the. formula:

R --CH M in which R stands for carbocyclic and and M represents the positive ion of a mono-halide of certain metals of groups HA and HE of the periodic system, particularly of magnesium, may be more appropriate. Such reagents are obtained according to known methods.

Furthermore, the ketones used as reagents for the preparation of the intermediates, particularly those of the formula in which R has the previously-given meaning and R represents a carbocyclic aryl radical, are known. Others, especially those, in which R represents a heterocyclic radical, such as those of the formula in which R A and Z have the previously-given meaning, may be prepared by treating an ester of the formula in which R represents a pyridyl radical, with a strong inorganic Lewis acid, and reacting the resulting phenolic kctone of the formula said phenolic ketone being preferably in the form of an alkali metal salt thereof, with a halide of the formula in which A and Z have the previously-given meaning and Hal represents a halogen atom, particularly chlorine.

The rearrangement of the carboxylic acid ester to the phenolic ketone in the presence of a strong inorganic Lewis acid may be carried out according to the procedure known as the Fries Rearrangement (A. H. Blatt, Organic Reactions, vol. I, p. 342, 1942 Wiley, New York). The strong inorganic Lewis acid is primarily a halide of a polyvalent metal, particularly aluminum chloride, aluminum bromide or stannicchloride; suitable solvents, if' necessary, are, for example, carbon disulfide, nitrobenzene, or analogous inert solvents.

The conversion of the phenolic ketone into the desired ketone material is preferably carried out by forming the alkali metal salt of the phenolic ketone, for example, by treatment with an alkali metal hydride, e.g. sodium hydride, or an -alkali metal amide, e.g. sodium amide, in a solvent, such as, for example, p-dioxane or analogous inert solvents suitable for the preparation of such metal derivatives. The resulting salt is then reacted with the halide of the formula r HalA--Z in which A, Z and Hal have the above-given meaning, in an inert solvent, such as, for example, in those used for the preparation of the salt.

A modification of the procedure for the preparation of the starting materials used in the manufacture of the compounds of this invention, particularly those of the formula in which R represents a heterocyclic aryl radical and R stands for a carbocyclic aryl radical and R and R have the previously-outlined meaning, comprises reacting a ketone of the formula R1 in which R has the above-given meaning, but represents primarily a heterocyclic aryl radical and R and R have the above-given meaning, with a reagent of the formula in which R may have the previously-given meaning, but represents primarily a carbocyclic aryl radical, and M stands for the positive ion of certain alkali metals (group IA of the periodic system) or, more especially, the positive ion of a mono-halide of certain metals of groups HA and HB of the periodic system, particularly of a mono-halide of magnesium.

Although certain heterocyclic compounds form alkali metal or Grignard reagents, such as, for example, 2-pyridyl magnesium chloride or 3-pyridyl magnesium bromide, carbocyclic aryl reagents are advantageously used as reagents in the above modification of the general procedure for the preparation of the starting materials. These reagents are prepared according to known methods, such as those previously described.

The ketones used as reagents in the above modification of the procedure for the preparation of the starting materials are known, or, if new, may be prepared according to known procedures. For example, ketones of the formula CHCO-R3 R4 in which R represents a heterocyclic aryl radical and R and K, have the previously-given meaning, may be prepared by reacting a reagent of the formula on n B; have the above-given meaning and of an alkali metal, such with the ester of an in which R and R, M represents the positive ion as sodium, or particularly lithium, acid of the formula in which R, has the previously-given meaning, with a lower alkanol, e.g. methanol or ethanol. The reaction is carried out under known conditions, which are in gen eral analogous to those employed in reactions involving organic metal reagents, as, for example, described hereinbefore.

alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, aqueous alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, or aqueous ammonia. A free base may be converted into its acid addition salts by reacting the former with one of the inorganic or organic acids mentioned hereinbefore, for example, by treating a solution of the free base in a solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol or isopropanol, an ether, e.g. diethylether, or a mixture of such solvents with the acid of a solution thereof. The salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions of salt formation; monoor poly-salts may be found depending on the number of salt-forming groups and/ or conditions of salt formation.

The quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the tertiary base with an ester formed by a hydroxylated aliphatic hydrocarbon compound and a strong inorganic or organic acid. Hydroxylated aliphatic hydrocarbon compounds may contain from one to seven carbon atoms, and esters thereof are more especially those with strong mineral acids. Such esters are specifically lower alkyl halides, e.g. methyl, ethyl, propyl or isopropyl chloride, bromide, iodide, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate, or lower alkyl lower hydroxy-allrane sulfonates, e.g. methyl Z-hydroxyethane sulfonate. The quaternizing reactions may be performed in the presence of a solvent; suitable solvents are more especially lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, butanol or pentanol, lower alkanones, e.g. acetone or methyl ethyl ketone, or organic acid amides, e.g. formamide or dimethylformamide. If necessary, elevated temperature, pressure and/ or the atmosphere of an inert gas, e.g. nitrogen, may be required.

Resulting quaternary ammonium compounds may be converted into the corresponding quarternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ainmonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be prepared therapeutically acceptable quaternary ammonium salts by reacting the former with acids, for example, with those outlined here inbefore for the preparation of the acid addition salts. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of a quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as hydrates; monoor poly-quaternary ammonium compounds may be formed depending on the number of tertiary amino groups present and/or the conditions of the quaternizing reaction.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following example is intended to illustrate the invention and is not to be construed as being a limitation thereon. Temperatures are given in degrees centigrade.

Example 1 2.1 g. of 1-[4-(Z-diethyltrminoethoxy)-phenyl] l-(4- methoxy-phenyD-Z-(2-pyridyl)-ethanol is dissolved in 50 ml. of dry ethanol. The solution is warmed to 50-60 and dry hydrogen chloride gas is passed through the solution for one-half hour. Heating is continued for one hour, the solvent is evaporated to leave the desired l-[4-(2-diethylaminoethoxy) phenyl] -l-(4-methoxy-phenyl)-2-(2- pyridyD-ethene hydrochloride. The salt may be converted into the free base by treatment of an aqueous solu tion with ammonia and extracting the free base with ether.

The starting material may be prepared as follows: A solution of 38 g. of aluminum chloride in 85 ml. of nitro; benzene may be obtained by heating a mixture thereof to 100", which is then cooled to 32.5 g. of phenyl 4- methoxy-benzoate is added at once and the reaction mixture is stirred for one hour at 80. The nitrobenzene is removed by steam distillation, the residue is diluted with a lzl-mixture of concentrated aqueous hydrochloric acid and water, and the acidic phase is extracted three times with ethyl acetate. The organic extract is washed with concentrated aqueous sodium chloride, treated with activated charcoal and dried over sodium sulfate. The solvent is removed under reduced pressure, a lzl-mixture of ether and pentane is added, and the crystalline material is filtered off. An additional crop. is obtained from the mother liquors; the combined crops are recrystallized twice from aqueous ethanol to yield the 4-hydroxy-4-methoxybenzophenone, Ml. 153-154; yield: 6.8 g.

To a solution of 6.8 g. of 4-hydroxy-4'-methoxy-benzophenone in 9i) ml. of toluene is added por-tionwise 1.42 g. of sodium hydride (52 percent pure) while stirring at room temperature. 28.8 ml. of a toluene solution of 2- dimethylaminoethyl chloride, containing 4.03 g. of the base (0.14 g. of the base in 1 ml. of toluene), is added; the reaction mixture is refluxed for three hours, then allowed to stand overnight. The solid material is removed by filtration, is washed with toluene and then discarded. The solvent is removed from the filtrate, ether is added and dry hydrogen chloride gas is passed through the solution. The oily precipitate is filtered oft, crystallized from a lzl-mixture of acetone and ether and recrystallized from ethyl acetate to yield the 4-(2-diethylaminoethoxy)- 4-methoxy-benzophenone hydrochloride, Ml. 139-140", yield: 5.2 g.

The hydrochloride salt is dissolved in a minimum amount of water, 2 N aqueous sodium carbonate is added until the solution reacts neutral, and the o-nganic material is then extracted with ether. The organic layer is washed with aqueous sodium chloride and dried over sodium sulfate, the solvent is evaporated and the 4-(2- diethylaminoethoxy)-4 methoxy benzophenone is distilled under reduced pressure. it solidifies and melts at 56-60"; yield: 4.52 g.

11.2 g. of a solution of n-butyl lithium in hexane, containing 1.768 g. of buty-l lithium (0.15 8 g. of butyl lithium in 1 ml. of hexane), is kept under a nitrogen atmosphere and cooled in an ice-bath. 2.57 g. of a-picoline in 20 ml. of benzene is added; the red solution is stirred for three hours at room temperature.

A solution of 4.52 g. of 4-(2-diethylaminoethoxy)-4- methoxy-benzophenone in 25 ml. of benzene is slowly given to the picoline lithium reagent; the mixture is stirred for three hours at room temperature and then allowed to stand overnight. The dark green solution is poured onto ice, the organic layer is separated and the aqueous phase is extracted three times with ether. The organic solutions are combined, washed with concentrated aqueous sodium chloride and dried over sodium sulfate. The solvents are removed to yield an orange oil. 1 g. of said oil, dissolved in a lcl-mixture of hexane and benzene, is chromatigraphed on an absorption column containing neutral aluminum oxide (activity Ill according to Brockmann) prewashed with hexane. A small amount of u-picoline is removed with the l:1-mixture of hexane and benzene; a yellow oil, representing the l-[4-(2-diethylaminoethoxy) penyl] 1 (4-methoxyphenyl)-2-(2- pyridyl)-ethanol is eluted with benzene. The IR-absorption spectrum reveals the. absence of a. carbonyl band at 1680 cmr and has the characteristic hydroxyl band at 3280 cm.- pyridyl band at 765 cm. and disubstituted phenyl band at 830 cmr Additional compounds of this invention, such as, for example,

l-(4-methyl-phenyl) -l-{4- [2-( l-pyrrolidino -ethoxy] phenyl}-2- Z-pyridyl) -ethene, 2- 4-chloro-phenyl) -l- [4- Z-dimethylaminoethoxy) phenyl]-l-(3-pyridyl)-ethene,

1- [4- (Z-dimethylaminoethoxy ).-phenyl] 1 3 -pyridyl) -2- Z-pyridyl -ethene,-

l-phenyl-l- [4- Z-dimethylarnino-Z-methyl-ethoxy) phenyl] -2- (Z-pyridyl ).-ethene,

l- [4- Z-diethylaminoethoxy) -phenyl] l- 4-dimethylamino-phenyl) -2- (4-pyridyl) -ethene,

l- [4- Z-diethylarninoethoxy) -phenyl] 1- (4-rnethoxyphenyl -2- 3-pyridazinyl) -ethene,

l- [4- Z-diethylaminoethyl) -phenyl] -1- 4-chloro-pheny1) 2- (2-pyrazinyl) -ethene,

or the salts of these compounds may be prepared according to the above-given procedure by dehydration from the corresponding l,l,2-tri-suostituted ethanol derivatives, which may be obtained by reacting the appropriate ketone with lithium or a magnesium monohalide derivative.

The l- [4- Z-diethylaminoethoxy) -phenyl] -1- 4-methoxy-phenyl)-2-(2-pyridyl)-l-propanol, obtained by treating the Z-ethyl-pyridine lithium derivative with 4-(2-diethylaminoethoxy)-phenyl 4-methoxy-phenyl ketone, may be dehydrated to the desired 1-[4-(2-diethylaminoethoxy) phenyl] 1-(4-methoxy-phenyl)-2-(2-pyridyl)-1- propene by passing dry hydrogen chloride gas through an ethanol solution of the starting material.

Any functional groups attached to portions of a resulting compound may be converted into other functional groups: for example, a nitro group may be reduced to an amino group, a nitro or a primary amino group may be reductively alkylated to form secondary or tertiary amino groups, and an amino group may be diazotized and converted to halogen according to the Sandmeyer method, etc.

What is claimed is:

l. A member of the group consisting of a compound of the formula:

in which one of the radicals R and R represents pyridyl and the other represents a member of the group consisting of pyridyl, phenyl, lower alkyl-phenyl, lower alkoxyphenyl, lower alkylenedioxy-phenyl, lower alkyl-mercapto-phenyl, nitro-phenyl, di-lower alkyl-amino-phenyl, halogeno-phenyl and polyhalogeno-lower alkyl-phenyl, R stands for phenyl substituted by the group of the formula -OA-Z, in which A represents alkylene which contains from two to three carbon atoms and separates the group Z from the oxygen atom by from two to three carbon atoms, and Z represents a member of the group consisting of N,N-di-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, and N,N-lower alkylene-imino, N,N-lower oxa-alkylene-imino, N,N- lower thia-alkylene-imino and N,N-lower aza-alkyleneimino, in which the alkylene radical contains from four to six carbon atoms, and the radical R represents a member of the group consisting of hydrogen and lower alkyl, the therapeutically acceptable acid addition salts thereof, and the quaternary lower alkyl ammonium salts thereof.

2. A compound of the formula:

in which R represents pyridyl, R stands for phenyl, A represents an alkylene radical which contains from two to three carbon atoms and separates the group Z from the oxygen atom by from two to three cat-eon atoms, and Z stands for N,N-di-1ower alkyl-amino.

3. A compound of the formula:

in which R represents pyridyl, R stands for lower alky'tphenyl, A represents an alkylene radical which contains from two to three carbon atoms and separates the group Z from the oxygen atom by from two to three carbon atoms, and Z stands for N,N-di-lower alkyl-amino.

4. A compound of the formula:

in which R represents pyridyl, R stands for halogenophenyl, A represents an alkylene radical which contains from two to three carbon atoms and separate the group 2 from the oxygen atom by from two to three carbon atoms, and Z stands for N,N-di-lower alkyl-amino.

5. -A compound of the formula:

in which R represents pyridyl, R stands for lower alkoxy-phenyl, A represents an alkylene radical which contains from two to three carbon atoms and separates the group Z from the oxygen atom by from two to three carbon atoms, and Z stands for N,N-di-lower alkyl amino.

6. 1 [4 (2 diethylaminoethoxy) phenyl] 1 (4- met'noXy-phenyl) -2-(2-pyridy1) -ethene.

References Cited in the file of this patent UNITED STATES PATENTS 2,566,360 Papa et a1. Sept. 4, 1951 2,703,324 Binkley et al. Mar. 1, 1955 2,768,207 Cheney et a1 Oct. 23, 1956 2,796,435 Goldberg et a1 Tune 18, 1957 2,914,529 Allen et al Nov. 24, 1959 2,914,561 Allen et a1 Nov. 24, 1959 2,914,564 Allen et a1 -2 Nov. 24, 1959 FOREIGN PATENTS 719,276 Great Britain Dec. 1, 1954 161,360 Australia Feb. 22, 1955 513,309 Belgium Aug. 30, 1952 OTHER REFERENCES Klingsberg: Pyridine and Derivatives, part 2, pages 425-5 and 434-5, Interscience Pub. Inc. (1961). 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 